Association of a presenilin 1 S170F mutation with a novel Alzheimer disease molecular phenotype

Alessandra Piccini, Gianluigi Zanusso, Roberta Borghi, Cristiana Noviello, Salvatore Monaco, Roberta Russo, Gianluca Damonte, Andrea Armirotti, Matteo Gelati, Renzo Giordano, Pamela Zambenedetti, Claudio Russo, Bernardino Ghetti, Massimo Tabaton

Research output: Contribution to journalReview article

39 Citations (Scopus)

Abstract

Objective: To report an ataxic variant of Alzheimer disease expressing a novel molecular phenotype. Design: Description of a novel phenotype associated with a presenilin 1 mutation. Setting: The subject was an outpatient who was diagnosed at the local referral center. Patient: A 28-year-old man presented with psychiatric symptoms and cerebellar signs, followed by cognitive dysfunction. Severe β-amyloid (Aβ) deposition was accompanied by neurofibrillary tangles and cell loss in the cerebral cortex and by Purkinje cell dendrite loss in the cerebellum. A presenilin 1 gene (PSEN1) S170F mutation was detected. Main Outcome Measures: We analyzed the processing of Aβ precursor protein in vitro as well as the Aβ species in brain tissue. Results: The PSEN1 S170F mutation induced a 3-fold increase of both secreted Aβ42 and Aβ40 species and a 60% increase of secreted Aβ precursor protein in transfected cells. Soluble and insoluble fractions isolated from brain tissue showed a prevalence of N-terminally truncated Aβ species ending at both residues 40 and 42. Conclusion: These findings define a new Alzheimer disease molecular phenotype and support the concept that the phenotypic variability associated with PSEN1 mutations may be dictated by the Aβ aggregates' composition.

Original languageEnglish (US)
Pages (from-to)738-745
Number of pages8
JournalArchives of Neurology
Volume64
Issue number5
DOIs
StatePublished - May 1 2007

Fingerprint

Presenilin-1
Alzheimer Disease
Phenotype
Mutation
Protein Precursors
Genes
Neurofibrillary Tangles
Purkinje Cells
Brain
Dendrites
Amyloid
Cerebral Cortex
Cerebellum
Signs and Symptoms
Psychiatry
Outpatients
Referral and Consultation
Outcome Assessment (Health Care)
Alzheimer's Disease
Gene

ASJC Scopus subject areas

  • Arts and Humanities (miscellaneous)
  • Clinical Neurology

Cite this

Piccini, A., Zanusso, G., Borghi, R., Noviello, C., Monaco, S., Russo, R., ... Tabaton, M. (2007). Association of a presenilin 1 S170F mutation with a novel Alzheimer disease molecular phenotype. Archives of Neurology, 64(5), 738-745. https://doi.org/10.1001/archneur.64.5.738

Association of a presenilin 1 S170F mutation with a novel Alzheimer disease molecular phenotype. / Piccini, Alessandra; Zanusso, Gianluigi; Borghi, Roberta; Noviello, Cristiana; Monaco, Salvatore; Russo, Roberta; Damonte, Gianluca; Armirotti, Andrea; Gelati, Matteo; Giordano, Renzo; Zambenedetti, Pamela; Russo, Claudio; Ghetti, Bernardino; Tabaton, Massimo.

In: Archives of Neurology, Vol. 64, No. 5, 01.05.2007, p. 738-745.

Research output: Contribution to journalReview article

Piccini, A, Zanusso, G, Borghi, R, Noviello, C, Monaco, S, Russo, R, Damonte, G, Armirotti, A, Gelati, M, Giordano, R, Zambenedetti, P, Russo, C, Ghetti, B & Tabaton, M 2007, 'Association of a presenilin 1 S170F mutation with a novel Alzheimer disease molecular phenotype', Archives of Neurology, vol. 64, no. 5, pp. 738-745. https://doi.org/10.1001/archneur.64.5.738
Piccini, Alessandra ; Zanusso, Gianluigi ; Borghi, Roberta ; Noviello, Cristiana ; Monaco, Salvatore ; Russo, Roberta ; Damonte, Gianluca ; Armirotti, Andrea ; Gelati, Matteo ; Giordano, Renzo ; Zambenedetti, Pamela ; Russo, Claudio ; Ghetti, Bernardino ; Tabaton, Massimo. / Association of a presenilin 1 S170F mutation with a novel Alzheimer disease molecular phenotype. In: Archives of Neurology. 2007 ; Vol. 64, No. 5. pp. 738-745.
@article{41a95028974d41338542be43438a78a9,
title = "Association of a presenilin 1 S170F mutation with a novel Alzheimer disease molecular phenotype",
abstract = "Objective: To report an ataxic variant of Alzheimer disease expressing a novel molecular phenotype. Design: Description of a novel phenotype associated with a presenilin 1 mutation. Setting: The subject was an outpatient who was diagnosed at the local referral center. Patient: A 28-year-old man presented with psychiatric symptoms and cerebellar signs, followed by cognitive dysfunction. Severe β-amyloid (Aβ) deposition was accompanied by neurofibrillary tangles and cell loss in the cerebral cortex and by Purkinje cell dendrite loss in the cerebellum. A presenilin 1 gene (PSEN1) S170F mutation was detected. Main Outcome Measures: We analyzed the processing of Aβ precursor protein in vitro as well as the Aβ species in brain tissue. Results: The PSEN1 S170F mutation induced a 3-fold increase of both secreted Aβ42 and Aβ40 species and a 60{\%} increase of secreted Aβ precursor protein in transfected cells. Soluble and insoluble fractions isolated from brain tissue showed a prevalence of N-terminally truncated Aβ species ending at both residues 40 and 42. Conclusion: These findings define a new Alzheimer disease molecular phenotype and support the concept that the phenotypic variability associated with PSEN1 mutations may be dictated by the Aβ aggregates' composition.",
author = "Alessandra Piccini and Gianluigi Zanusso and Roberta Borghi and Cristiana Noviello and Salvatore Monaco and Roberta Russo and Gianluca Damonte and Andrea Armirotti and Matteo Gelati and Renzo Giordano and Pamela Zambenedetti and Claudio Russo and Bernardino Ghetti and Massimo Tabaton",
year = "2007",
month = "5",
day = "1",
doi = "10.1001/archneur.64.5.738",
language = "English (US)",
volume = "64",
pages = "738--745",
journal = "Archives of Neurology",
issn = "0003-9942",
publisher = "American Medical Association",
number = "5",

}

TY - JOUR

T1 - Association of a presenilin 1 S170F mutation with a novel Alzheimer disease molecular phenotype

AU - Piccini, Alessandra

AU - Zanusso, Gianluigi

AU - Borghi, Roberta

AU - Noviello, Cristiana

AU - Monaco, Salvatore

AU - Russo, Roberta

AU - Damonte, Gianluca

AU - Armirotti, Andrea

AU - Gelati, Matteo

AU - Giordano, Renzo

AU - Zambenedetti, Pamela

AU - Russo, Claudio

AU - Ghetti, Bernardino

AU - Tabaton, Massimo

PY - 2007/5/1

Y1 - 2007/5/1

N2 - Objective: To report an ataxic variant of Alzheimer disease expressing a novel molecular phenotype. Design: Description of a novel phenotype associated with a presenilin 1 mutation. Setting: The subject was an outpatient who was diagnosed at the local referral center. Patient: A 28-year-old man presented with psychiatric symptoms and cerebellar signs, followed by cognitive dysfunction. Severe β-amyloid (Aβ) deposition was accompanied by neurofibrillary tangles and cell loss in the cerebral cortex and by Purkinje cell dendrite loss in the cerebellum. A presenilin 1 gene (PSEN1) S170F mutation was detected. Main Outcome Measures: We analyzed the processing of Aβ precursor protein in vitro as well as the Aβ species in brain tissue. Results: The PSEN1 S170F mutation induced a 3-fold increase of both secreted Aβ42 and Aβ40 species and a 60% increase of secreted Aβ precursor protein in transfected cells. Soluble and insoluble fractions isolated from brain tissue showed a prevalence of N-terminally truncated Aβ species ending at both residues 40 and 42. Conclusion: These findings define a new Alzheimer disease molecular phenotype and support the concept that the phenotypic variability associated with PSEN1 mutations may be dictated by the Aβ aggregates' composition.

AB - Objective: To report an ataxic variant of Alzheimer disease expressing a novel molecular phenotype. Design: Description of a novel phenotype associated with a presenilin 1 mutation. Setting: The subject was an outpatient who was diagnosed at the local referral center. Patient: A 28-year-old man presented with psychiatric symptoms and cerebellar signs, followed by cognitive dysfunction. Severe β-amyloid (Aβ) deposition was accompanied by neurofibrillary tangles and cell loss in the cerebral cortex and by Purkinje cell dendrite loss in the cerebellum. A presenilin 1 gene (PSEN1) S170F mutation was detected. Main Outcome Measures: We analyzed the processing of Aβ precursor protein in vitro as well as the Aβ species in brain tissue. Results: The PSEN1 S170F mutation induced a 3-fold increase of both secreted Aβ42 and Aβ40 species and a 60% increase of secreted Aβ precursor protein in transfected cells. Soluble and insoluble fractions isolated from brain tissue showed a prevalence of N-terminally truncated Aβ species ending at both residues 40 and 42. Conclusion: These findings define a new Alzheimer disease molecular phenotype and support the concept that the phenotypic variability associated with PSEN1 mutations may be dictated by the Aβ aggregates' composition.

UR - http://www.scopus.com/inward/record.url?scp=34249099116&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=34249099116&partnerID=8YFLogxK

U2 - 10.1001/archneur.64.5.738

DO - 10.1001/archneur.64.5.738

M3 - Review article

C2 - 17502474

AN - SCOPUS:34249099116

VL - 64

SP - 738

EP - 745

JO - Archives of Neurology

JF - Archives of Neurology

SN - 0003-9942

IS - 5

ER -